Preclinical gene correction of hemophilia A

A型血友病临床前基因校正

基本信息

批准号：
7393720
负责人：
HAIG H. KAZAZIAN
金额：
$ 39.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-06 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7393720
关键词：
7,7&apos -dimethoxy-(4,4&apos -bi-1,3-benzodioxole)-5,5&apos -dicarboxylic acid dimethyl ester A Mouse Adult Animal Model Animals Antibodies Antibody Formation B-Lymphocytes Canis familiaris Capsid Clinical Trials Complementary DNA Condition Development Dose Effectiveness Gene Delivery Hemophilia A Immune response Infusion procedures Intravenous Light Liver Mediating Monitor Morbidity - disease rate Numbers Plasma Portal vein structure Proteins Rate Risk Route Safety Serotyping Staging T-Lymphocyte Testing Therapeutic Transgenes Viral Viral Packaging Virus Work adeno-associated viral vector compare effectiveness gene correction gene therapy gene therapy clinical trial improved inhibitor/antagonist intravenous administration neutralizing antibody novel pre-clinical prevent recombinant antihemophilic factor VIII response size success transmission process vector

项目摘要

DESCRIPTION (provided by applicant): This proposal sets the stage for clinical trials of gene therapy for hemophilia A. Here we concentrate on the use of adeno-associated viral (AAV) vectors with new capsid serotypes for liver directed gene therapy in a large animal model, namely, the hemophilia A dog. This work builds upon our previous success in "curing" the hemophilia A mouse using FVIII gene delivery in two new AAV serotypes, AAV8 and AAV9. Our studies in hemophilia A dogs, while more modestly successful, have also been encouraging with both new AAV serotypes. In this application, we evaluate further these AAV serotypes, beginning with delivery of FVIII cDNA in heavy chain and light chain vectors. We test responses at two different doses for both AAV8 and AAV9, and compare intraportal to intravenous routes of vector administration, We then go on to develop an effective, smaller single chain vector that can be produced in high titers, and test this single chain vector using the best combination of serotype, dose, and route of administration. We will also carry out therapy with our best conditions in young dogs, in an effort to initiate treatment before the onset of serious morbidity and also to prevent inhibitor formation to rFVIII used for conventional therapy. Lastly, we will determine whether FVIII can be readministered to dogs using a different serotype vector from the vector used in the original virus infusion. In all of these studies significant efforts will be made to test the safety of the new AAV vectors, concentrating on studies of neutralizing antibodies, development of transaminitis, and germline transmission of virus. At the end of these studies, we expect to have discovered treatment conditions that consistently produce long-term therapeutic levels of FVIII (>10% of normal) in a large animal, the hemophilia A dog. These results should make clinical trials with AAV vectors an appropriate next step.

描述（由申请人提供）：该提案为血友病A基因治疗的临床试验设定了阶段A。在这里，我们集中于使用与新的肝脏血清型在大型动物模型中使用新的capsid capsid血清型的腺体相关病毒（AAV）载体（AAV）载体。这项工作是基于我们以前在使用FVIII基因递送在两个新的AAV血清型AAV8和AAV9中“治愈”小鼠的成功中的成功。我们在血友病A狗的研究虽然更为谦虚，但也令人鼓舞的是两种新的AAV血清型。在此应用中，我们进一步评估了这些AAV血清型，从重链和轻链矢量中的FVIII cDNA开始。我们测试了AAV8和AAV9的两种不同剂量的反应，并比较了对矢量给药的静脉内途径进行比较，然后我们继续开发有效的，较小的单链矢量，可以在高滴度中产生，并使用血清型，剂量，剂量和给药的最佳组合来测试该单链矢量。我们还将在幼犬中进行最佳疾病的治疗，以便在严重发病率发作之前开始治疗，并防止抑制剂形成用于常规治疗的RFVIII。最后，我们将使用与原始病毒输注中使用的载体不同的血清型载体对狗的FVIII确定。在所有这些研究中，将尽力测试新的AAV载体的安全性，集中于中和抗体的研究，跨氨基炎的发展和病毒的生殖线传播。在这些研究结束时，我们希望发现治疗条件，这些治疗条件始终产生长期治疗水平的FVIII（>正常的10％），在大动物，血友病的一只狗中。这些结果应使与AAV矢量的临床试验成为适当的下一步。